1. Technical Field
The present invention relates to an optical imaging apparatus and method, and more particularly, to an ultraslow light and nondegenerate phase conjugation-based real-time, non-invasive, in vivo deep-tissue optical imaging apparatus and optical imaging method, which use a nonlinear medium having four energy levels and at least three optical pulses that resonate or near-resonate between the energy levels of the optical medium. Herein, the term “deep-tissue” means a tissue having a depth on the order of cm.
2. Related Art
In in vivo optical imaging, light scattering in a heterogeneous substance such as bio-tissue is the biggest problem that interferes with the application of optical tomography to the medical field by distorting optical images and significantly decreasing signal-to-noise ratios.
Optical coherence tomography (OCT; http://en.wikipedia.org/wiki/Optical coherence tomography; http://www.zeiss.com/) is the only examine in which optical imaging is applied to the eye's retina and cornea which require only images having a shallow bio-tissue depth of 1 mm or less. To overcome the problem of light scattering in bio-tissue, ultrasound has been applied to optical imaging techniques such as ultrasound-modulated optical tomography (UOT; Interface Focus Vol. 1, p. 632 (2011)) and photoacoustic tomography (PAT; Interface Focus Vol. 1, p. 602 (2011)). Herein, the ultrasound is the key to increase in vivo imaging depth (Interface Focus Vol. 1, p. 503 (2011)). The reason is because ultrasound is weakly absorbed by bio-tissue or weakly scattered in bio-tissue. Meanwhile, light generally shows good characteristics in the contrast of images. Thus, to maintain the in vivo deep-tissue imaging advantage of ultrasound and add good contrast of light, it is required to combine ultrasound with light waves. The resulting ultrasound-modulated light waves enhance both resolution and imaging depth in optical imaging. Herein, to distinguish the ultrasound-modulated optical signal from the background noises of other optical signals to thereby increase signal-to-noise ratios, a Fabry-Perot interference system (Appl. Phys. Lett. Vol. 55, p. 1612 (1989); Opt. Lett. Vol. 34, p. 3445 (2009)) or a spectral hole burning technique (Appl. Phys. Lett. Vol. 93, p. 011111 (2008)) have been applied.
In recent years, ultrasound-modulated optical tomography techniques have been intensively studied to apply degenerate optical phase conjugation at the same wavelength to optical imaging, and the phase conjugation is a nonlinear optical phenomenon having time-reversible properties, which accurately reverses the propagation direction of light waves (Nature Communications Vol. 6, p. 5904 (2014)). The phase conjugation has the property of accurately and perfectly removing image distortions caused by all phase variations generated in scattering media, and thus the imaging resolution can be increased to the ultrasonic wavelength limits.
In recent years, in order to apply phase conjugation to ultrasound-modulated optical tomography to thereby increase resolution and depth, a photorefractive material or a spatial light modulator (SLM) has been used. Furthermore, because scattered optical signals are very weak, optical phase conjugate waves can be artificially generated using a spatial light modulator, and the intensity thereof can also be increased (Nature Photon. Vol. 9, p. 243 (2015). Although the switching time of the spatial light modulator has been shortened owing to the development of electronic devices for the past ten years, a spatial light modulator-based ultrasound-modulated optical tomography technique has not yet been applied to real-time in vivo optical imaging due to the slow imaging time. More specifically, there is an inversely proportional relationship between the individual pixel size of the spatial light modulator, which determines the imaging resolution, and the pixel number which determines the total switching time. To make phase conjugate waves for each of ultrasound-modulated optical signals incident to each pixel of the spatial light modulator, the signals should be processed by a computer, and the processing time is limited by the frame rate of the spatial light modulator, and thus an SLM having 1,000,000 pixels does not reach even kHz (Hamamatsu LCOS-SLM). Thus, when a bio-tissue volume of 10 cm×10 cm×10 cm is scanned by ultrasound-modulated optical tomography with a resolution of 0.1 mm at a kHz rate, the total scan time is 10,000 seconds (about 166 minutes) or more. Namely, due to the temporal limit of the spatial light modulator, apart from imaging depth, even the latest ultrasound-modulated optical tomography technology cannot be applied to optical medical diagnosis.
Meanwhile, in the case of photo-refractive materials, the optical phase conjugation conversion efficiency thereof is generally about 1% or less, and for this reason, the actual application of the photo-refractive material is very limited due to a low signal-to-noise ratio and a small etendue caused by a narrow incident angle (R. W. Boyd, Nonliner Optics (Academic Press, 1992) Ch. 6). Usually, the phase conjugation conversion efficiency of the photo-refractive material can be increased using high-intensity input light. However, in ultrasound-modulated optical tomography for in vivo deep-tissue imaging, a low-intensity ultrasound-modulated optical signal is generated, and for this reason, the photo-refractive material has a limitation in that it cannot be applied to optical medical imaging.
In photoacoustic tomography (PAT), the detection of ultrasound that is generated based on the thermal expansion of bio-tissue by induction of light wave absorption is the core of optical imaging (Science Vol. 335, p. 1458 (2012)). To make photoacoustic tomography useful, light-absorbing substances, for example, erythrocytes, should be activated. In other words, photoacoustic tomography cannot be used for general purposes such as medical imaging diagnosis. Furthermore, to apply photoacoustic tomography to in vivo deep-tissue imaging, femtosecond high-power energy should be used, and the reason is to overcome scattering in tissue and to allow a sufficient amount of light to reach a desired point (Opt. Lett. Vol. 30, p. 507 (2005). Although cm-deep PAT optical imaging potentials have recently been reported in in vivo models (phantom tissues), photoacoustic tomography is generally applied to in vivo tissue as shallow as skin deep by use of hemoglobin or a fluorescent substance (Science Vol. 335, p. 1458 (2012)).
Ultraslow light is a typical nonlinear quantum optical phenomenon, the group velocity of light waves can be controlled by subjecting a resonant dispersive medium to non-absorption transmission by use of electromagnetically induced transmission (EIT: Physics Today Vol. 50, No. 7, p. (1997)) or spectral hole burning effect (Nature Communications Vol. 5, p. 3627 (2014); Opt. Exp. Vol. 17, p. 9369 (2009)). In 1999, Harris and his research team observed that the group velocity of light in a Bose-Einstein condensate was reduced up to 17 m/s (Nature Vol. 397, p. 594 (1999). In 2002, Ham and his research team observed that the group velocity of light in a Pr3+-doped Y2SiO5 (Pr:YSO) solid medium was 30 m/s (Phys. Rev. Lett. Vol. 88, p. 023602 (2002). These two first observations of ultraslow light are based on EIT, and the EIT is a typical quantum interference effect which results from two-photon coherence in a three-level photorefractive medium that interacts with two resonant light pulses. Ham et al. also observed ultraslow light by the spectral hole burning method rather than the EIT, and the group velocity of the observed light was about 300 m/s (Opt. Exp. Vol. 17, p. 9369 (2009)). It is generally difficult to achieve EIT in solid media, because the Rabi frequency of light should be larger than the inhomogeneous broadening of the corresponding resonant frequency, and this condition is not achieved in almost all solid media by use of general commercial lasers. Ham et al. modified a Pr:YSO solid medium by spectral hole burning in 1997, which is the world's first modification, and observed EIT in 1997, and also observed and reported ultraslow light completely separated from signal light pulses, in 2002 (Opt. Communi. Vol. 144, p. 227 (1997); Phys. Rev. Lett. Vol. 88, p. 023602 (2002)).
A general phase conjugation phenomenon is obtained using light having the same wavelength in a two-level or four-level degenerate energy system. The physical principle in this general degenerate phase conjugation or degenerate four-wave mixing process is the density grid of light coherence-based medium. Thus, the phase conjugation linewidth is limited by the physical constant of the medium, that is, decay rate or dipole moment (oscillator strength). Herein, the phase conjugation conversion efficiency can be increased merely by increasing the intensity of light pumping. However, phase matching conditions in the medium result in narrowing of the angle variation of input signal light, thereby limiting the application of the light. Furthermore, in ultrasound-modulated optical tomography, the intensity of modulated light is very weak due to in vivo scattering, and thus the intensity of phase conjugation is also very low.
Meanwhile, a nondegenerate phase conjugation phenomenon is produced based on two-photon-induced spin coherence (i.e., moving coherence grating) in a three-level energy system that interacts with two difference light waves. Ham et al. observed nondegenerate four-wave mixing (Opt. Lett. Vol. 22, p. 1138 (1997)) in 1997 by use of a solid medium and also observed nondegenerate optical phase conjugation (Phys. Rev. A Vol. 59, p. R2583 (1999)), which are the world's first observations. Herein, the linewidth of the nondegenerate phase conjugation is determined by the spin phase shift time. Unlike degenerate phase conjugation, EIT-based nondegenerate phase conjugation is based on the fact that the intensity of input signal light is very weak, and this condition almost perfectly satisfies the limit condition of ultrasound-modulated optical tomography, that is, the weak ultrasound-modulated optical signal condition. The conversion efficiency of nondegenerate phase conjugation is limited by two-photon-induced spin phase coherence according to the EIT intensity. Very importantly, nondegenerate phase conjugation is amplified by the control of atomic density to a certain level and the control of the EIT intensity (Opt. Lett. Vol. 20, p. 982 (1995); Opt. Lett. Vol. 24, p. 86 (1999).
The most interesting phenomenon in nondegenerate optical phase conjugation is ultraslow light-enhanced conversion efficiency (Phys. Rev. A Vol. 68, p. 041801(R) (2003)). This is because temporal/spatial energy density is increased by ultraslow light, and this energy density is increased by slow constant h (h=c/vg, vg=group velocity of ultraslow light), and solid slow constant h observed by Ham et al. is 107 (Phys. Rev. Lett. Vol. 88, p. 023602 (2002).
Ham et al. recently observed photon-echo as ultraslow light-amplified phase conjugation, and the size of the observed photo-echo was several thousand times greater than that of conventional photo-echo (OSA NLO 2015 conference, W4A, Hawaii, USA (2015)). In a rubidium vapor EIT system, Scully et al. observed slow light-enhanced nondegenerate phase conjugation (Phys. Rev. Lett. Vol. 82, p. 5229 (1999)). Harris et al. first identified and demonstrated slow light-enhanced nondegenerate four-wave mixing processes (Rev. Lett. Vol. 82, p. 4611 (1999)).
Photodynamic therapy is a method for treating diseases (including cancer) using light, and uses a photosensitizer or a photosensitizing agent. According to the principle of photodynamic therapy, when a photosensitizer is excited with light having a specific wavelength, the photosensitizer activates the surrounding oxygen so as to kill the surrounding cells (Nature Reviews Cancer Vol. 5, p. 380 (2003). Thus, slow light-amplified nondegenerate phase conjugate waves may be applied not only to optical imaging, but also to photodynamic therapy. Up to now, a real-time noninvasive photodynamic therapy method has not been reported.